Lysyl-tRNA synthetase produces diadenosine tetraphosphate to curb STING-dependent inflammation

Guerra, J, Valadao, A-L, Vlachakis, D, Polak, K, Vila, IK, Taffoni, C, Prabakaran, T, Marriott, AS, Kaczmarele, R, Houel, A
et al (show 9 more authors) (2020) Lysyl-tRNA synthetase produces diadenosine tetraphosphate to curb STING-dependent inflammation. SCIENCE ADVANCES, 6 (21). eaax3333-.

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Inflammation is an essential part of immunity against pathogens and tumors but can promote disease if not tightly regulated. Self and non-self-nucleic acids can trigger inflammation, through recognition by the cyclic GMP-AMP (cGAMP) synthetase (cGAS) and subsequent activation of the stimulator of interferon genes (STING) protein. Here, we show that RNA:DNA hybrids can be detected by cGAS and that the Lysyl-tRNA synthetase (LysRS) inhibits STING activation through two complementary mechanisms. First, LysRS interacts with RNA:DNA hybrids, delaying recognition by cGAS and impeding cGAMP production. Second, RNA:DNA hybrids stimulate LysRS-dependent production of diadenosine tetraphosphate (Ap<sub>4</sub>A) that in turn attenuates STING-dependent signaling. We propose a model whereby these mechanisms cooperate to buffer STING activation. Consequently, modulation of the LysRS-Ap<sub>4</sub>A axis in vitro or in vivo interferes with inflammatory responses. Thus, altogether, we establish LysRS and Ap<sub>4</sub>A as pharmacological targets to control STING signaling and treat inflammatory diseases.

Item Type: Article
Depositing User: Symplectic Admin
Date Deposited: 10 Jun 2020 07:50
Last Modified: 18 Jan 2023 23:49
DOI: 10.1126/sciadv.aax3333
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